2-formyl-delta2-corticoids



United States Patent 3,086,013 Z-FORNIYL-A -CORTICOIDS Albert Bowers and James C. Orr, Mexico City, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Sept. 15, 1961, Ser. No. 138,267 26 Claims. (Cl. 260-23955) OHzOR In the above formulas, X represents B-hydroxy or keto; Y represents hydrogen, fluorine or chlorine; Z represents hydrogen, fluorine, chlorine or methyl; R represents hydrogen, a-methyl, fl-methyl, a-hydroxy or u-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms; and R and R each represent hydrogen or the residue of a hydrocarbon radical containing up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated and including aromatic groups.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, 'cyclopentylpropionate, aminoacetate and fl-chloropropionate.

The novel compounds of the present invention are prepared by the following equation:

0M6 OH ,I'

at: o IV I III I Z 2 HzC-O I OH: 0-0

ornoH /CH3 5 ---o ---on M x= M I Y Y In the above formulas, R X, Y and Z have the same meaning as previously set forth; R represents a-methyl, fi-methyl or a-acyloxy of the type described hereinabove. Me represents methyl and Ac represents the acyl group of a hydrocarbon carboxylic acid of less than 12 carbon atoms and is preferably the acetyl radical.

In practicing the process outlined above, the starting corticoid compound (I) is treated with formaldehyde in the presence of acid thus obtaining the corresponding 17,20;20.2l-bismethylenedioxy derivative which is hydrogenated with, for example, hydrogen in the presence of 5% palladium on charcoal catalyst or lithium in ammonia, thus furnishing the saturated 3-keto derivative (II). Treatment of this compound with ethyl formate in the presence of an alkali metal hydride, such as sodium hydride, and subsequent reaction of the formed sodium salt with an acid, affords the corresponding 2-hydroxymethylene-3-keto derivative (III). Methylation of the hydroxymethylene group with a suitable agent such as diazomethane, furnishes the respective 2-methoxymethylene 3-keto compound (IV). Reduction of the 3-keto group, preferably with sodium borohydride and subsequent treatment of the formed S-hydroxy compound with a very mild acid, yields the corresponding 2-formyl-l7,20;20,21- bismethylenedioxy-A -allopregnene derivative (V). Treatment of a 2-formyl-17,20;20,2l-bismethylenedioxy-M- allopregnen-ll-one (V; X=O) with excess acetic anhydride and acetyl chloride aflords the Z-acetoxymethylene- 17,20;20,2l bismethylenedioxy A allopregnen 11- one derivative (VII). This reaction causes the ready acetylation of the hydroxyl groups that may be present in the molecule, as for example, a 16a-hydroxyl group (R =x-OH), thus furnishing the corresponding acetoxy compounds (VII: R =a-acetoXy). Treatment of compound (VII) with N-bromosuccinimide, affords the corresponding 2-formyl-4/8-bromo derivative (VIII).

An alternate procedure to produce this compound is by direct treatment of the corresponding 2-formyl-17,20;- 20,21-bismethylenedioxy-Alallopregnene derivative (V) with N-bromosuccinimide.

This derivative upon selective dehydrohalogenation of the 4,8-bromo .substituent, as for example, with calcium carbonate in dimethylformamide, for a period of time of the order of 5 minutes at reflux temperature, furnishes the respective Z-formyI-A -pregnadiene derivative (IX). The 16u-acetoxy group that may be present (IX; R ot-acetoxy) is conventionally saponified with a base to furnish the free 16a-hydroxyl.

Following a second sequence of reaction, a 2-formyl- 17,20;20,21 bismethylenedioxy A allopregnen 11,8- 01 compound (V: X=;8-OH) upon treatment with excess acetic anhydride and excess acetyl chloride, affords the corresponding 2-acetoxymethylene-17,20;20,2l-bismethylenedioxy-A -allopregnen-1 1,8-01-1 l-acetate derivative (XI) When there are present in the molecule other hydroxyl groups, such as a lfia-hydroxyl (V: X=B-OH; R oc-OH), there is obtained the corresponding acetoxy derivative, in this instance the l6a-acetoxy compound (XI; R =a-acetoxy).

Treatment of compound (XI) with N-bromosuccinirnide affords the corresponding 2-formyl-4,8-bromo-A allopregnene derivative (XII), which upon selective dehydrohalogenation such as described hereinabove, furnishes the respective 2-forrnyl-l7,20;20,2l-bismethylenedioxy-A -pregnadien-1lB-ol-11-acetate derivative (XIII). Reaction of this compound with lithium aluminum hydride affords the reduction of the formyl group and the hydrolysis of the ester groups present in the molecule, thus yielding the 2-hydroxyrnethyl-17,20;20,2l-bismethy1- enedioxy-A -pregnadien-l113-01 compound (XIV). Selective oxidation of the allylic alcohol group with 1.1 molar equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature and for a period of time of the order of 3 hours, furnishes the corresponding 2- forrnyl-17,20;20,2l-bismethylenedioxy A pregnadienllfi-ol-derivative (XV).

The above described 2-forrnyl-17,20;20,2l-bismethylenedioxy derivatives (V, IX, XV) are hydrolyzed to the corresponding 2-fO1'II1y1-170t, 21-di0l-20-one derivatives (VI, X, XVI) by treatment in an acid medium, as for example 60% formic acid at reflux temperature, for a period of time of the order of 1 hour.

The above mentioned compounds with a primary hydroxyl such as the 2tl-hydroxyl, and/or a secondary hydroxyl, such as the l6vt-hydroxyl group, are conventionally acylatecl in pyridine with an acylating agent, as for example acetic anhydride or caproic anhydride, furnishing the corresponding C-21-acyloxy or C-21, 16adiacyloxy derivatives.

The above mentioned compounds with a hydroxyl group at C-16oc and at C-17a are converted into the 16oz, 170t-CYC1IC acetal or 16a, 170t- CYCHC ketal by reaction with an aldehyde or ketone such as acetone, formaldehyde, paraldehyde, acetaldehyde, benzophenone, acetophenone, methyl ethyl ketone, diethyl 'ketone and other similar aldehydes and ketones in the presence of an acid catalyst such as perchloric acid or hydrochloric acid.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention: 1

Example I Following the abovete'chnique, there were treated the sponding products hereinafter set forth:

Starting compound Product 6a,16B-dimethyl-N-pregnen-l711,21-

diol 3,11,20-trione.

6a,16B-dimethyl N-pregnene-llfi,

17a,21-trio1-3,20 dione.

6a-chloro-9a-fiuoro-A -pregnene- 16a,17a,21-triol-3,11,20-trione.

Qa-fiuoro-M-pregnen-llfl,1601,1701,

21-tetro1-3,20-dione.

Hydrocortisone fia-methyl-lfia-hydroxy-hydrocortisone.

Example II I A solution of 4 g. of 16a-methyl-6a-fiuoro-17,20;2(),21-

bismethylenedioxy-M-pregnene-3,ll-dione in cc. of dioxane-ether (1:1) was added in a steady stream to a solution of 0.4 g. of lithium in 400 cc. of anhydrous liquid ammonia with good stirring. At the end of the addition, the blue color was discharged by the addition of 20' g. of ammonium chloride and the ammonia was allowed to evaporate. The product was extracted with ether, washed with water, dried and the ether evaporated to aiford a gum which was absorbed from 200 cc. of benzene onto 200 g. of alumina. Elution with benzene-ether afforded a product which upon recrystallization from acetonehexane gave 16a-methyl-6a-fluoro-l7,20,20,21-bismethylenedioXy-all0pregnane-3,1 l-dione.

The starting compounds listed below were treated following the above procedure, thus furnishing the corresponding products hereinafter set forth:

Starting compound Product 16a-methyl-6a,9a-difluorolfia-methyl-fia, a-difluoro- 17, 20; 21,21-bismethylenedioxy- 17 20; 20,21-bismethylenedioxy- A -pregnene-3,l1-di0ne. allopregnane-3,11-dione. 16wmeth LGa-tllloro-Qa-chloro- 16a-methyl-6zx-fluoro-9a chloro- 17,20; 20,21-b1smethy1enedioxy- 17, 20; 20,21-bismctbylenedioxy- A -pregnene-3,11-dione. allopreguane3,1l-dione.

lfia-ElGlIhYI-Ga-fill010 17,20; 20,21-bisrnethylenedioxyallopregnan-11fl-ol-3-one.

Starting compound Final product one. 17,20; 20,21-bismethylenedioxy- A -pregnen-11B-o1-3-one. 6a-methyl-17,20; 20,21-

bismethylenedioxy-A pregnen- 11fl,16a-diol-3-one.

Example III To a solution of 3 g. of 16ot-1I16thYl-6oc-fi11010-17,20;

17,20;20,21-bismethylenedioxy-allopregnane-3,ll-dione.

Following exactly the same procedure, there were treated the starting compounds hereinafter listed, furnishing the corresponding products disclosed below:

Starting compound Product 16a-methyl-6a-fluoro-9a-ch1oro- 17,20; 20,21-bismcthylenedioxyallopregnane-3,11-dione.

16mmethyl-fia-fiuoroemchloro- 17,20; 20,21-bismethylonedioxyalloprcgnan-11B-ol-3-ono.

6u,16,9-dimothyl-17.20; 20,21-

bisrncthylcnedioxy-allopregnanc- 3,11-dine.

6a,16fl-dimethyl-17,20; 20,21-

bismethylenedioxyallopregnan- 11flo1-3-one.

oa-chloro-oa-fluoro-lmt); 20,21-

bisrnethylcnedioxy-ailopregnan- 16a-ol-3,11-dione.

9a-fluoro-l7,20; 20,21- bisrnethylonedioxy-allopregnano- 115,16a-diol-3-one.

9a-fill010-17,20; 20,21-bismethylenedioxy-alloprcgnan- 16tx-01-3,11-di0[10.

17,20; 20,21-bismethylenodioxyallopregnan-llfi-ol-Zl-one.

Ga-methyl-17,20; 20,21-bisn1ethylcncdioxy-alloprognano- 11,8,16a-diol-3-one.

2-l1ydroxymothylene-lfia-methyl- 6a,9a-di[luoro-17,20; 20,21- bismethylenedioxyallopregmane-3,11-di0ne. 2-hydroxymcthylone-lfia-methyh GZX-nUQI'OQLZChIQI'O-TI,20; 20,21-bismethy1enedioxyallopregnaue-3,l1-dione. 2-hydroxymethyleno-lfia-mothyl 6cr-fl1l010-17,20; 20,21- bisrnethylenedioxy-allopregnan- 11,801-3-one. 2-11ydroxymcthylone-lfia-methyl- 6a,9a-ditluoro-17,20; 20,21- bismcthylenedioxy-allopregnan- 11,8-ol-3-one. 2-hydroxymothylene'lGQ-methylfia-fluoro-Qa-ehloro-I7,20; 20,21- bismethylcnedioxy-nlloprcguan- 1lB-0l-3-onc. 2*hydroxymcthylene-IGB-mothyl- 6a,9a-difiuoro-l7,20; 20,21- bismethylenedioxy-allopregnane- 3,11diono. 2-hydroxymethylenedGB-rnethyl- 6a,9a-dlfill01'O-17,2Q; 20,21- bismethylenedioxy-allopregnan- 11,8ol-3-one. 2rl1ydroxymethyleno6a,16,6!-

dimethyl-17,20; 20,21- bismcthylenedioxy-alloprognauc- 3, 11- dione 2-hydroxymethyiene tiadtifldimethy1-17,20; 20,21- bisrnethylenedioxy-allopregnan- 11B-ol-3-0ne. Z-hydroxymethylenefia-chloro- 9a-fiuoro-17,20; 20,21- bismethylcnedioxy-allopregnan- 16a-0l-3,l1-(1l0110. 2-hydroxymethylene-fia-ohloro- 9a-fi11010-17,20; 20,21-

bisniethylenedioxy-allopregnano- 65 1113,16zx-dl0l-3-0H6. Z-hydroxymethylonea-fiuoro- 17,20; 20,21-bismethylcnedioxyallopregnane-l15,16a-di0l-3-0110. 2hydroxyrncthylene-ou-fluoro- 17,20; 20,2l-bismethylcncdioxyallopregnan-loa-ol-iy,ll-dione. 2-11ydroxymethylene-17,20; 20,21-

blsrnethylenedioxy-allopregnan- 11fl-ol-3one. 2-11ydroxymcthylenefiu-methyl- 17,20; 20,21-bismethylonedioxyallopregnanc-llfi,lfia-diol- 3-0110.

8 Example IV To a solution of 3 g. of 2-hydroxymethylene-16amethyl c fluoro 17,20;20,21 bismethylenedioxy-allopregnane-3,11-dione in 50 cc. of methylene chloride, there were added an excess of diazomethane in ether (obtained from nitrosomethylurea) and a few drops of methanol. The reaction mixture was kept at room temperature for 18 hours. The excess reagent was decomposed with acetic acid. The resulting mixture was poured into water, the organic layer washed to neutral and evaporated to dryness. Recrystallization from acetone-hexane afforded 2 methoxymethylene 16oz methyl 6a-iluoro- 17,20 ;20,2l-bisniethylenedioxy-allopregnane-3, 1 l-dione.

By the same method, there were treated the starting compounds listed below, thus yielding the corresponding products hereinafter disclosed:

Starting compound Product 2-hydroxymothylene16amethyl-6a,9a-difluoro-l7,20; 20, 21-bismethyleucdioxy-alloprcgname-3,11-dione.

2-hydroxyrnethylene-1fiat-methyl- Ga-fillOtO-9a-Ci110IO-l7,20; 20,21- bismothylencdioxy-alloprcgnano- 3,11-dionc.

2-hydroxymothylone-loa-mcthyl- (im-fi1101O-17,20; 20,21-bismethy1 onedioxy-allopregnan-llB-ol-tione. Z-hydroxymothylene-lGet-methyl- Ga,90z-dllll10r0-17,20; 20,21-bismethylenedioxy-alloprognan-1lflol-3-one. 2-hydroxymethylene-lfia-mcthylfia-fluoro-Qa-chloro-17,20; 20,21- bisrnethylencdioxy-allopregnan- 11B-ol-3-one. 2-hydroxymethy1ene-1S S-methyl- 6zx,9zx-dlfi1lO!O-17,20; 20,21-bismethylcnedioxy-alloprognanc- 3,11-di0nc. 2-hydroxymothyleno-16 -methyl- 6a,9a-diiluoro-l7,20; 20,21-bismethylenedioxy-allopregnanllfi-ol-B-onc. 2-hydroxymcthylenc-fiadofldirncthy1'17,20; 20,21-bismethylonedioxy-alloprognanc-3,11- dione. Z-hydrOXymethylene-GaJ- dimethyl-l7,20; 20,21-bismcthylonedioxy-allopregnan-llfi-ol-B- one. 2-hydroxymcthy1eno-6a-ehloro-9afluoro-17,20; 20,21-bismethylcncdlOXY-fillOpICgllflH-lfizz-013,11- dione. 2-hydroxyrnethylene-fia-chloro-9athrow-17,20; 20,2l-bismethylcnedioxy-allopregnane-l1,8,10a-di01- 3-one. 2-hydroxymethylene-M-fluorm 17,20; 20,21-bismethylenedioxyallopregnane-l1B,16rz-diol-3-one. Z-hYdIOXyIIlGlIhYIGHO-Qa-HUOI'O- 17,20; 20,21-bismethylencdioxyal1oprognan-16a-o1-3J1-dione. 2-hydroxymcthylene-l7,20; 20,21-

bismethylenedioxy-allopregnan- 113-ol-3-one. 2-hydr0xymcthylene-fia-mcthyl- 17,20; 20,21-bismcthylenedioxyalloprcgnans-1113,16a-di01-3-0no.

one. 2-methoxymethylenodoa-rncthyl- 61,9udifluoro-17,2O; 20,21-bismethylenedioxy-allopregnan-llflo1-3-ono. 2-methoxymethylone-10a-methylfia-fiuOIO-Qa-ChlOlOJ7,20; 20,21- bismcthylenedioxy-allopregnan- 11fl-ol-3-oue. Z-methoxymethylene-ltip-methyl- 6a,9a-diflu010-17,20; 20,21-bismothylencdioxy-allopregnanc- 3,11-dionc. 2-mcthoxyrnethylene-1fiB-methyl- 6a,9a-dlfi110lO-l7,20; 20,21-bismethylenedioxy-alloprcgnan- 1119-0130110. 2-methoxymethylone-oadfifldhnothyl-17,20; 20,21-bismethylenedioxy-ellopregnanc-S,11- dionc. Z-mcthoxymethylene-6 m?- dimethyl-17,20; 20,21-bisn1cthylonedioxy-allopregnan-l1 3-01-3- one. 2-1710thOXYmOlShYIGDQ-Ga-OhlOI'WQamicro-17,20; 20,21-bismethylcnedioxy-al]oprcgnan-16a-0l-3,11- dione. 2-methoxymethy1ene-6a-ch1oro-9afluoro-17,20; 20,21-bisrnethylonedroxy-allopregnanc-llfidowdi01- 3-one. 2-rncthoxymethylene-flu-fluoro- 17,20; 20,21-bisrnethylenedioxyallopregnane-l13,16a-dio1-3-0n0. 2-rncthoxyrncthylene-tla-fluoro- 17,20; 20,21-bismethylcnedioxyalloprcgnan-lfia-ol-B,ll-dione. 2-'n ethoxymothylonc-17,20; 20,21-

b1smethylencdioxy-alloprcgnau- 115-ol-3-0nc. 2-mothoxymethylenc-fia-methyl- 17,20; 20,21-bismethylenedioxyalloprcgnane-llfi,lGa-diol3-onc.

Example V A solution of 2 g. of sodium borohydride in 5 cc. of water was added to an ice-cooled solution of 2 g. of 2- methoxymethylene 16oz methyl 60c fluorol7,20;20,21 bismethylenedioxy allopregnane 3,11-

l6u-methyl 60: fluoro 17 ,20;20,21 bismethylenedioxy- A -allopregnen-1 l-one.

The starting compounds hereinafter listed were treated following the above technique thus yielding the corresponding products disclosed below:

Starting compound Product one. 2-methoxymethy1ene-1Got-methyl- 6m,9a-difill0r0-17,20; 20,2l-bismethylenedioxy-allopregnan- 11B-ol-3-one. 2-methoxymethylene 1Got-methyl- 6cz-fiI101'0-9a-Chl0l0-17,20; 20,21- bismethylenedioxy-allopregnan- 11fi-ol-3-one. 2-methoxymethylene-l(SB-methyl- 6a,9a-diflu0lO-17,2D; 20,21-bismethylenedioxy-allopregnane- 3,11-dione. 2-methoxymethylene-lofl-methyL 6a,9a-difiu0ro-l7,20; 20, 21-bisn1ethylenedioxy-allopregnan-11,8- ol-3-one. 2-methoxymethylene-6a,16,9-

dimethyl-l7,20; 20,21-bismethylenedioxy-allopregnane-3,11- dione. z-inethoxymethlene-fia,16 3- dimethyl-17,20; 20,21-bismethylenedioxy allopregnan-l15-01-3- one. 2-methoxymethylene-fia-chloro- 9a-fll1010-17,20,' 21,21-bismethylenedioxy-allopregnan-lGaol-3,11- dione. 2-methoxymethyleneoa-chlom- 9a-fluoro-17,20; 20,21-bismethylenedioxy-allopregnane-l1fl,16adiol-3-0ne. 2-methoxymethylene-9a-fluoro- 17,20; 20,21-bismethy1enedioxyallopregna-ne-l1 3,16a-diol-3-one. Z-methoxymethylene-tla-fiuoro- 17,20; 20,21-bismethylenedioxyallopregnau-l6a-ol-3,11-dione. 2-methoxymethlene-17,20; 20,21

bisinethylenedioxy-allopregnan- 1lB-ol-3-one. 2emethoxymethylene-fia-methyl- 17,20; 20,21-bismethylenedioxyallopregnanc-11fi,16a-diol-3-one.

2-1'ormyl-16a-methyl-6a,9a-

difiuorol7,20; 20,21-bismethylenedioxy-A -allopregnen-11-one.

2-formyl-16a-methy1-6a,9a-

difluro-17,20; 20,21-bismethylenedioxy-N-allopregnen-llB-ol.

2-formyl-16B-mefind-611,971-

difluoro-17,20; 20,21-bismethylenedioxy-n -allopregnen-ll-one.

2-formy1-16 3-methy1-6a-9a,

difiuoro-17,20; 20,21-bismethylenedi0xy A -a1lopregnen-llB-ol.

2-f0rrnyl-6a,16B-dimethyl-17,20; 20,21-bisn1ethylenedioxy-M- allopregnen-ll-one.

2Jermyl-6u,16B-dimethyl-17,20; 20,21-bismethylenedioxyn allopregnen-llfl-ol.

2-formyl-6a-chlcro-9a-fiuoro-17,2O 20,2l-bismethylenedioxy-A allopregnen-lMol-ll-one.

2-formyl-9a-fluoro-17,20; 20,21-

bismethylenedioxy-N-allopregnene-llfiJM-diol.

2-formyl-17,20; 20,21bismethy1- enedioxy-N-allopregnen-l1B- ol-3-one.

2-formyl-6a-methyl-17,20; 20,21-

bisrnethylenedioxy-n -allopregnene-1lfl,16a-dio1-3-one.

Example VI pregnen-l l-one.

Using the same conditions described above, there were treated the starting materials listed below, thus afior'ding the corresponding products hereinafter set forth.

Starting compounds Final Products 2-acetoxymethylene-16tat-methyl- 6a,9a-difluoro-l7,20; 20,21- bismethylenedioxy-N- allopregnen-ll-one.

2-acetoxymethylene-ltia-methyl- 6a-fill0rO-9a-0h10l0-17,20; 20,21- bismethylenedioxy-N- allopregnen-ll-one 2-acetoxymethylene-lfia-methyl- 6a-fluoro-17,20; 20,21- bismethylenedioxy-A allopregnen-l1B-ol-11-acetate.

Starting compounds Final Products 2-formyl-9a-fiuoro-17,20; 20,21-

bismethylenedioxy-A allopregnen-lfiwol-ll-one.

2-formyl-17,20; 20,21-

bisrnethylenedroxy-A allopregnen-llfi-ol-li-one.

z-formyLfia-methyl-l7,20; 20,21-

bismethylenedioxy-A 'allopregnene-11B,16z1-di01-3-one.

2-acetoxymethylenedfia-methyl- 6u,9a-difil10rO-17,20; 20,21- bisrncthylenedioxy-A allopregnen-llfi-ol-ll-acetate. 2-a-acetoxymethy1ene-1(ta-methyl- 6a-fi110l0-9u0hl0l0-17,20; 20,2140ismethylenedioxy-A allopregnen-llfl-ol-ll-acetate. 2-acetoxymethylene-lG/S-methyl- 6cz,9a-diflllO10-17,20; 20,21- bismethylenedioxy-M- allopregnen-ll-one. 2-acetoxymethyleneJGB-methyl- 6a,9a-diflu0T0-17,20; 20,21- bismethylenedioxy-A allopregnene-llfl-ol-ll-acetate. Zaeet0xymethy1ene-6a,16fidimethyl-17,20; 20,21- bismethylenedioxy-A allopregnen-ll-one. 2-aeetoxymethylenefi lofldimethyl-17,20; 20,21- bismethylenedioxy-A allopregnen-11B-ol-11-aeetate. 2-acet0xymethylene-6a-chloro- 9a-fl110l0-17,20; 20,21- bismethylenedioxy-A allopregnen-lfia-ol-ll-one-lfiacetate. Z-acetoxyrnethylene-M-chloro- 9a-fluoro-17,20; 20,21- bismethylenedioxy-A allopregnene-llfi, lfia-diOl-ll, lfi-diaeetate. 2-acetoxymethylene-tla-fiuoro- 17,20; 20,21-bismethylenedioxy- A -allopregnene-llfl, lfia-diOl- 11,16-diacetate. 2-acetoxymethylene-tla-fluoro- 17,20; 20,21-bisrnethylenedioxyn -allopreg'nendfia-oLll-one lfi-acetate. 2-acetoxyrnethylene-17,20; 20,21-

bismethylenedioxy-A allopregnen-llB-ol-ll-acetate. 2-acetoxymethylene-firz-methyl- 17,20; 20,21-bismethylenedioxy- A -allopregnene-l1fl,16a-di01- 11,16-diacetate.

Example VII A solution of 1 g. of 2-acetoxymethylene-lGar-methyl- 6a-fluoro-17,20;20,21-A -allopregnen-1l-one in 20 cc. of dioxane was treated with 1.5 cc. of a 0.5 N per-chloric acid solution and then, there was added over a period of 30 minutes 1.1 molar equivalents of N-chlorosucoinimide. The operation was conducted with constant stirring and at 5 C. The resulting mixture was further stirred for 2 hours; Water was added, the formed precipitate filtered off and dried. Crystallization from acetone-hexane afforded 2-formyl-16u-methyl-4fl-bromo 6a fluoro-17,20;20,21- bismethylenedioxy-n -allopregnen-1 l-one.

1 g. of the above compound was refluxed with 1 g. of calcium carbonate and 50 cc. of dimethylformamide for 5 minutes, the mixture was filtered, the solvent evaporated under reduced pressure and the residue crystallized from acetone-hexane to aiford 2-f-ormyl-l6ot-methyl-6ot-fiuoro- 17,20;20,2l-n -pregnadien-l l-one.

The starting compounds listed below were treated following the above technique, furnishing the final products hereinafter disclosed:

Starting compound Final product Starting compound Final Product Z-acctoxymethyleneMid-methyl- 6a,9a-difil10rO-17,20 20,21- bismcthylenedloxy-N- allopregnen-ll-onc.

acetate. 2-formyl-6a-methyl-17,20; 20,2l-b1smcthylencdioxy-A -pregnadien- 11536044110141,lfi-diacetatc.

Example VIII -A solution of 1 g. of 2-formyl-16a-methyl-6a-fluoro- 17,20;20,21-bismethylenedioxy A pregnadien-llfi-olll-acetate in 50 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate; the combined organic solutions upon evaporation yielded a crude material which was purified by crystallization from acetone-hexane, thus giving Z-hydroxymethyl- 16oz methyl 60c fluoro-17,20;20,2l-bismethylenedioxy- A -pregnadien-1 1 5-01.

The starting compounds listed below were treated by the same procedure furnishing the products hereinafter set forth:

Starting compound Product lid-01. 2-hydroxymethyl-lfia-rnethyl-damethylenedioXy-A -prcgnadicn- Example IX A mixture of 1 g. of Z-hydroxymethyl-l6a-methyl-6afluoro-l7,20,20,21-bismethylenedioxy A pregnadien- 12 -01 in 20 cc. of dioxane, and 1.1 molar equivalents of 2,3-dichloro-5,6-dicyano 1,4 benzoquinone was kept at room temperature for 3 hours. The hydroquinone formed during the reaction was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 20 g. of alumina. Crystallization from acetone-hexane gave 2-formyl-l6a-methyl-6a-fluorol7,2O;20,2l-bismethylenedioXy-A' -pregnadien-l 15-01.

Following the above technique, there were treated the starting compounds listed below, thus affording the products indicated hereafter:

Product 2-hydroxymcthyl-IGa-methyl-Ga,

Qa-difluoro-N, 20; 20, 21- bismethylencdizxy-A' -pregnadicn- 11 15-01. 2-hydroxymethyl-l(Ba-methyl- 6cx-fl110l0-9ouClJlOIO-l7, 20; 20, 21- bismethylencdioxy-N pregnadicn-IGB-ol. 2-hydroxyrnethyl-lfiB-rnethyl- 6a, 9a-difluoro-17, 20; 20, 21- bismethylcncdioxy-n pregnadien-llB-ol. Z-hydroxymcthylta, 16H- dirnctliyl-l7,20; 20, 21- bismethylenedioxy-A -prcgnadien-llfl-ol. 2-l1ydroxyrnethyl omchloro- 9a-fiUOT0-17, 20; 20, 2L bismethylcncdioxy-A pregnadicne-llfl, lfia-diol. 2hyd1'0. ;yrn ethyl-Qwfiuoro- 17, 20; 20, 2l-bisn1ethylencdioxyprcgnadlone-11:3, lda-diol. 2-hydroxymethy1-l7, 20; 20, 21-

bismeth ylenediory-A pregnadien-llB-ol.

nadicn-llfl-ol. 2-iorInyl-lGBaucthyl-Ga, 9a-

difluoro-17, 2U; 20, 21- bis methylcnedioxy-M pregnadicn-lfl-ol. Z-forrnyl-Ga, 15/3- dimcthyl-17,

20; 20, 2l-bismcthylcnedioxy- A -pregnadicn-nB-ol.

Example X A solution of l g. of 2-formy1-6rx-chloro-9a-fluoro-17, 20; 20, 21 bisrnethylenedioxy-A -pregnadien-l6a-ol-llone-l6-acetate in 50 cc. of methanol was refluxed for 3 hours with 500 mg. of potassium hydroxide dissolved in 1 cc. of water; it was then poured into ice water, the precipitate collected, washed with water to neutral and dried. Recrystallization from methylene chloride-ether afforded 2 formyl 6oz chloro-9a-chl0r0-l7,20;20,21-bismethylenedioxy-A -pregnadien-1604-01-1l-one.

When applying this procedure to 2-f0l'l'l'lYl-90t-flll0IO-17, 2O;20,21-bismethylenedioxy-A -pregnadien 16a 01-11- one-16-acetate, there was obtained 2-forrny1-9wfluoro-17, 20;2l bismethylenedioXy-A -pregnadien 16a o1 11- one-l6-acetate.

Example XI 1 g. of Z-formyl 16cc methyl-6a-fluoro-17,20;20,21- bismethylenedioxy-M-allopregnen-ll-one was heated on a steam bath with 20 cc. of 60% formic acid for 20 minutes, cooled, diluted with water and the precipitate was collected, washed with water, dried, and recrystallized from acetone-hexane, thus affording 2-formyl-16oc-methyl- Starting compound Product Starting compound Product 2.4. regnadien-l1-one.

2-formyl-A -allopregnene- 11fi.17a,21-trio1-20one.

Example XII A mixture of 1 g. of 2-forrnyl-16a-methyl-6a-fluoroA Example XIII Using exactly the same conditions described in Example XII, except that acetic anhydride was substituted by propionic anhydride, caproic anhydride, cyclopentylpropionic anhydride and benzoyl chloride, there were obtained respectively the corresponding propionates, caproates, cyclopentylpropionates and benzoates of the above mentioned starting compounds of Example XII.

Example XIV To 120 cc. of acetone containing 1 g. of 2-formyl-6w chloro-9a-fluoro-A -allopregnene-16a,17 x,2l tri0l-1l,20- dione, produced in Example XI, were added 30 drops of 78% perchloric acid. After 1 hour at room temperature 30 drops of pyridine were added and the resulting solution was evaporated to dryness under reduced pressure. There were then added 30 cc. of water to the residue and it was then extracted several times with 80 cc. of ethyl acetate. The combined extracts were Washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. The residue upon trituration with methanol gave a crude 16,17-acetonide. Recrystallizations from the same solvent furnished the acetonide of 2-formyl 6OL-Ch1OI'O-9OL-fluOI'O-A a1lopregnene-16a,17a,

21-triol-1 1,20-dione.

By dollowing the same procedure, there were treated the corresponding products hereinafter disclosed:.

Starting compounds Final Products 1113, 21-tetr01-20-one.

The acetonide of 2-formyl-9afluoro-A -allopregnene-l1B, 16:2, 170:, 21-tetrol-20-one.

The acetonide of 2-formyl-9afiuoro-A -alloprcgnene-16u, 17a, 21-triol-11, 20-dione.

The acctonide of 2-torn1yl-6achloro-Qa-fiuoro-A e-pregnadiene-llB, 16a, 17a, 21-tetr0l-20- one.

Starting compounds Final products fiuoro-A -preg-nadiene-lda, 17a, 2l-triol-l1, -dione.

The aeetonide of 2-formyl-6amethyl-N-alloprognene-llfi, 16a, 17a, 21-tetrol-20-one.

diene-loa, 17a, 21-triol-11-20- dione.

2-formyl fia-methyl-A -allopregnone-116, 160:, 1701, 21-tetro1-20- one.

Example XV Using the same procedure described in Example XIV except that acetone was substituted by benzaldehyde, cyclohexanone and paraformaldehyde, there were obtained respectively the corresponding 16a,17a-benzylidenedioxy, 16a, l7oc-cyclohexanone ketal and 160:,l7zxmethylenedioxy derivatives of the starting compounds of Example XIV.

Example XVI The final products described in Examples XIV and XV were converted into the corresponding ZI-acetates, 21- propionates, 21-caproates, 2l-cyclopentylpropionates and 2l-benzoates in accordance with the methods described in Examples XII and XIII.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, ot-rnethyl-p-rnethyl, a-hydroxyl, and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; X is selected from the group consisting of keto and fl-hydroxyl; Y is selected from the group consisting of hydrogen, fluorine and chlorine, and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

2. 2 formyl 16a:me thyl-6a-fluoro-A -allopregnene- 17a,21-diol-11,20-dione.

3. 2 formyl-16vc-methyl-6et,9ot-diflu0ro-A allopregnene-17a,21-diol-1 1,20-dione.

4. 2 formyl-16a-methyl-6a-fluoro-9a-chloro A -allopregnene-17a,21-diol-11,20-dione.

5. 2 formyl 16a-methyl-6a,9a-difiuoro-A -allopregnene-l15,17a,21-triol-20-one.

6. 2 formyl 16a-methyl-Ga-fluoro-9a-chloro-A -allopregnene-l 1fl,17a,21-triol-20-one.

7. 2 formyl 16p-methyl-6u,9a-difluoro-M-allopregnene-l1,8,17a,21-triol-20-one.

8. 2 formyl 16B-methy1-6a,9a-difiuoro-A -a1lopregnene-17a,2l-diol-11,20-dione.

9. 2 formyl 6a,16p-dimethyl-A -allopregnene-17,2ldiol-11,20-dione.

10. 2 formyl 6a,16,8-dimethyl-A -allopregnene-1lfl, 17a,21-tri0l-20-one.

ll. 2 formyl Ga-chloro-9a-fluoro-A -allopregnene- 16c:,17cc,21-t1l0111,20-Cll0l16.

12. 2 formyl 6oz-chloro-9a-fiuoro-A -allopregnene 11/3,16a,l7a,2l-tetrol-20-one.

13. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, ot-lllfilhYl, fl-methyl, a-hydroxyl, and an tat-hydrocarbon carboxylic acyl group of less than 12 carbon atoms; X is selected from the group consisting of keto and fl-hydroxyl; Y is selected from the group consisting of hydrogen, fluorine and chlorine; and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

14. 2 formyl 16u-methyl-fia-fiuoro-n -pregnadienc- 17a,21-diol-l1,20-dione.

15. 2 formyl C-mBthy1-60t,90t-dlfillO1'O-A -plCgnadiene-17a,2l-diol-11,20-dione.

16. 2 formyl 16tit-methyl-6ot-fiu0l'O-9a-Ch10IO-A pregnadiene-17u,21-diol-11,20-dione.

17. 2 formyl 16ot-methyl-6or,9a-difluoro-A -pregnadiene-l lfl,l7a,21-triol-20-one.

18. 2 formyl 1604-1116thYl-6oc-fiu010-9oc-Chl0rO-A pregnadiene-l1/3,17a,21-triol-20-one.

20. 2 formyl 16(3-methy1-6a,9a-difluoro-A -pregnadiene-17a,21-diol-l1,20-dione.

21. 2 formyl 6a,16,8-dimethyl-A -pregnadiene-17a, 21-diol-11,20-dione.

22. 2 formyl 6a,16/3-dimethyl A -pregnadienel 1,8,17a,21-tri0l-20-0I16.

23. 2 formyl-6a ch1oro-9a-fluoro-A -pregnadiene- 16a,l7a,21-triol-l1,20-dione.

24. 2 formyl 6 x-chloro-9a-fiuoro-A -pregnadicne- 11B,16a,17a,21-tetrol-20-one.

25. A compound of the following formula:

wherein X is selected from the group consisting of keto and B-hydroxyl; Y is selected from the group consisting of hydrogen, fluorine and chlorine; Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R and R are each selected from the group consisting of hydrogen and a hydrocarbon radical containing up to 8 carbon atoms.

OHzOR 17 26. A compound of the following formula:

OHaOR -0 R o i Y o 12 0 HALE) 18 wherein X is selected from the group consisting of keto and fi-hydroxyl; Y is selected from the group consisting of hydrogen, fluorine and chlorine; Z is selected irorn the group consisting of hydrogen, fluorine, chlorine and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylie acyl group of less than 12 carbon atoms; and R and R are each selected rfrom the group consisting of hydrogen and a hydrocarbon radical containing up to 8 carbon atoms.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 26. A COMPOUND OF THE FOLLOWING FORMULA: 